Compositions for treatment of xerostomia and for tooth treatment

ABSTRACT

The present application provides an oral care composition comprising:
         a) emu oil;   and one or more of the following:   b) one or more emulsifying agents;   c) one or more protease enzymes;   d) one or more soluble calcium phosphate remineralizing agents;   e) one or more whitening agents.

Throughout this application, certain publications are referenced inparentheses. Full citations for these publications may be foundimmediately preceding the claims. The disclosures of these publicationsin their entireties are hereby incorporated by reference into thisapplication.

BACKGROUND

Xerostomia is the subjective sensation of dry mouth and may beassociated with diminished or deficient salivary secretion. Saliva andsalivary flow help prevent the accumulation of microorganisms in themouth (Nederfors et al. 1997). Saliva is also necessary for effectiveremineralization of teeth (Narhi et al. 1999). Salivary flow initiatesdigestion of foods and help dissolve and remove food particles from themouth. Saliva also lubricates the mucosa of the mouth, facilitatingspeech, eating, and swallowing and preventing mechanical injury to thesurfaces of the mouth. Xerostomia is a commonly occurring disorder andresults in higher risk for oral complications.

Diverse symptoms and consequences have been associated with xerostomia.Symptoms include halitosis, soreness, oral burning, difficultyswallowing, and altered taste sensation. Xerostomia also causes dentaldisorders including oral mucous membrane ulcers, dental caries andperiodontosis, oral infections and respiratory tract infections.

Known causes of xerostomia include various diseases causing organicchange of salivary glands; pathological changes of salivary glandscaused by systemic diseases; damaged salivary glands owing toradiotherapy; HIV infection (AIDS); secretory hypofunction owing toaging; and effects of administration of various drugs. Mental fatigue orstress may also be factors.

Various drugs also result in xerostomia as a side effect. Examples ofdrugs that may cause xerostomia include: diuretics such astrichloromethiazide and furosemide, hypotensors such as reserpine andclonidine hydrochloride, anticholinergic agents such as atropinesulfate, and antihistamines such as chlorphenylamine maleate. Otherexamples thereof include various expectorant/cough suppressants,anti-Parkinson drugs, psychotropic drugs, antidepressants,tranquilizers, muscle relaxants, opiates and other narcotics.Radiotherapy has become increasingly important for treating malignanttumors in oral surgery and otolaryngology fields, and almost inevitablycauses damage to salivary glands by ionizing radiation. This damage canresult in especially severe xerostomia. Medications are believed to beresponsible for a significant proportion of cases of xerostomia,particularly in the elderly (Nedefors et al. 1997). The list of drugsthat are believed to affect saliva levels includes more than 400 agents(Narhi at al. 1999).

Xerostomia is more common among older people and among women (Hochberget al. 1998; Nederfors et al. 1997). In one study xerostomia wasreported in 21.3% of the men and in 27.3% of women (Nederfors et al.

-   1996). In another study of elderly type-2 diabetic individuals, the    prevalence of dry mouth was found to be 25% (Borges B C et al.    2010). The prevalence of xerostomia in varied populations ranges    from 0.9% to 46% (Orellana, M. F. et al. 2006).

There are various therapies for the treatment of xerostomia, althoughmany result in unfavorable side effects and limited efficacy (Cassolato,S. F. et al. 2003; Gupta, A. et al. 2006; Silvestre-Donat, F. J. et al.2004). For example, malic and citric acid have been used as salivarystimulants. However, they had a demineralizing effect on tooth enamel(Anneroth, G. et al. 1980; Davies, A. N. 2000).

SUMMARY

The present application provides an oral care composition comprising:

-   -   a) emu oil;    -   and one or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents;    -   e) one or more whitening agents.

The present application provides an oral care composition for whiteningteeth comprising one or more whitening agents, wherein the compositionis formulated as a bilayer tablet comprising:

-   -   (i) a rapidly disintegrating layer; and    -   (ii) a slowly eroding layer,    -   wherein the one or more whitening agents are each oxidizing        agents and are each present only in the rapidly disintegrating        layer.

The present application provides an oral care composition comprising:

-   -   a) one or more omega fatty acids;    -   and one or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents;    -   e) one or more whitening agents.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Bilayer Tablet comprising a rapidly disintegrating layer and aslowly eroding layer.

FIG. 2. Bilayer Tablet comprising a rapidly disintegrating core and aslowly eroding outer layer.

DETAILED DESCRIPTION

The present application provides an oral care composition comprising:

-   -   a) emu oil;    -   and one or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents;    -   e) one or more whitening agents.

In one embodiment, the composition comprising:

-   -   a) emu oil;    -   and two or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents;    -   e) one or more whitening agents.

In one embodiment, the composition comprising:

-   -   a) emu oil;    -   and three or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents;    -   e) one or more whitening agents.

In one embodiment, the composition comprising:

-   -   a) emu oil;    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents;    -   e) one or more whitening agents.

In one embodiment, an oral care composition consisting essentially of:

-   -   a) emu oil;    -   and one or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents;    -   e) one or more whitening agents.

In one embodiment, the composition consisting essentially of:

-   -   a) emu oil;    -   and two or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents;    -   e) one or more whitening agents.

In one embodiment, the composition consisting essentially of:

-   -   a) emu oil;    -   and three or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents;    -   e) one or more whitening agents.

In one embodiment, the composition consisting essentially of:

-   -   a) emu oil;    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents;    -   e) one or more whitening agents.

In one embodiment, the composition wherein one or more of the proteaseenzymes are selected from the group consisting of papain, trypsin,chymotrypsin, aminopeptidase, carboxypeptidase, pepsin, and cathepsin.

In one embodiment, the protease enzyme is stem bromelain. The stembromelain provides an anti-inflammatory effect.

In one embodiment, 50 mg of stem bromelain is present in thecomposition.

In one embodiment, the composition wherein the one or more whiteningagents are selected from the group consisting of carbamide peroxide andhydrogen peroxide.

In one embodiment, the composition wherein the one or more solublecalcium phosphate remineralizing agents are selected from the groupconsisting of dibasic calcium phosphate, monocalcium phosphate,tricalcium phosphate, and tetracalcium phosphate.

In one embodiment, the composition wherein the soluble calcium phosphateremineralizing agent is amorphous calcium phosphate.

In one embodiment, the composition wherein the one or more emulsifyingagents are phospholipids.

In one embodiment, the composition wherein the phospholipids arelecithin.

In one embodiment, the composition wherein the lecithin is dairy-freeand/or egg-free. A dairy-free or egg-free lecithin provides acomposition with a longer shelf life in comparison to lecithin sourcedfrom egg or milk.

In one embodiment, the composition wherein the lecithin is soy lecithin.In one embodiment, the composition wherein the lecithin is sourced fromsoybeans.

In one embodiment, the composition wherein the composition furthercomprises an isomalt.

In one embodiment, the composition wherein the isomalt is selected fromthe group consisting of galenIQ™ 720 and galenIQ™ 721.

In one embodiment, the composition wherein the composition furthercomprises a disintegrating agent.

In one embodiment, the composition wherein the disintegrating agent iscrospovidone.

In one embodiment, the composition wherein the composition furthercomprises magnesium stearate.

In one embodiment, the composition wherein the composition furthercomprises glycerin.

In one embodiment, the composition wherein the composition furthercomprises fluoride.

In one embodiment, the composition wherein the remineralizing agent iswhite in color.

In one embodiment, the composition is formulated as a tablet, a bilayertablet, a multilayer tablet, chewing gum, a toothpaste, a lozenge, apowder, a gel, a viscous gel, an ointment, a cream, a liquid, amouthwash, or a candy.

In one embodiment, the composition is formulated as a round flat tabletor a round concave tablet.

In one embodiment, the composition is formulated as a bilayer tablet.

In one embodiment, the composition wherein the bilayer tablet comprisesa rapidly disintegrating layer and a slowly eroding layer.

In one embodiment, the composition wherein the one or more whiteningagents are present only in the rapidly disintegrating layer.

In one embodiment, the composition wherein the emu oil and the one ormore proteases are present only in the slowly eroding layer.

In one embodiment, the composition wherein the one or more whiteningagents are present only in the rapidly disintegrating layer; and the emuoil and the one or more proteases are present only in the slowly erodinglayer.

In one embodiment, the composition wherein the rapidly disintegratinglayer comprises carbamide peroxide in an amount between 0.1 to 10.0% byweight.

In one embodiment, the composition wherein the rapidly disintegratinglayer comprises carbamide peroxide in an amount of 1.0% by weight.

In one embodiment, the composition wherein the slowly eroding layercomprises emu oil in an amount between 0.1 to 15% by weight.

In one embodiment, the composition wherein the slowly eroding layercomprises emu oil in an amount of 10% by weight.

In one embodiment, the composition wherein the slowly eroding layercomprises papain in an amount between 0.1 to 20% by weight.

In one embodiment, the composition wherein the slowly eroding layercomprises papain in an amount of 10% by weight.

The present application provides a method of treating a subjectsuffering from xerostomia which comprises administering to the subject,in an amount effective to treat the xerostomia, a composition of thepresent application.

In one embodiment, the method wherein the composition further whitensteeth in the subject's mouth.

In one embodiment, the method wherein the composition furtherremineralizes teeth in the subject's mouth.

In one embodiment, the method wherein the composition further whitensand remineralizes teeth in the subject's mouth.

In one embodiment, the method wherein the composition further reducesdental sensitivity of the subject.

In one embodiment, the method wherein the composition further treatsdental caries of the subject.

In one embodiment, the method wherein the subject is a human.

In one embodiment, the method wherein the subject is a non-human animal.

In one embodiment, the method wherein the subject has an autoimmunedisease, diabetes, Sjögren's syndrome, or has recently undergoneradiation therapy or chemotherapy.

In one embodiment, the method wherein the subject is concurrently takingone or more medications that causes xerostomia.

The present application provides an oral care composition for whiteningteeth comprising one or more whitening agents, wherein the compositionis formulated as a bilayer tablet comprising:

-   -   (i) a rapidly disintegrating layer; and    -   (ii) a slowly eroding layer,    -   wherein the one or more whitening agents are each oxidizing        agents and are each present only in the rapidly disintegrating        layer.

In one embodiment, an oral care composition for whitening teethconsisting essentially of one or more whitening agents, wherein thecomposition is formulated as a bilayer tablet comprising:

-   -   (i) a rapidly disintegrating layer; and    -   (ii) a slowly eroding layer,    -   wherein the one or more whitening agents are each oxidizing        agents and are each present only in the rapidly disintegrating        layer.

In one embodiment of the bilayer composition, the composition whereinthe one or more whitening agents are selected from the group consistingof carbamide peroxide and hydrogen peroxide.

In one embodiment of the bilayer composition, the composition whereinthe whitening agent is carbamide peroxide and is present in an amountbetween 0.1 to 10.0% by weight of the disintegrating layer.

In one embodiment of the bilayer composition, the composition whereinthe whitening agent is carbamide peroxide and is present in an amount of1.0% by weight of the disintegrating layer.

In one embodiment of the bilayer composition, the composition furthercomprising one or more of the following:

-   -   a) emu oil;    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents.

In one embodiment of the bilayer composition, the composition furthercomprising two or more of the following:

-   -   a) emu oil;    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents.

In one embodiment of the bilayer composition, the composition furthercomprising three or more of the following:

-   -   a) emu oil;    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents.

In one embodiment of the bilayer composition, the composition furthercomprising each of the following:

-   -   a) emu oil;    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents.

In one embodiment of the bilayer composition, the composition furthercomprising each of the following:

-   -   a) emu oil;    -   and one or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents.

In one embodiment of the bilayer composition, the composition whereinthe emu oil, the one or more emulsifying agents, and the one or moreprotease enzymes are present only in the slowly eroding layer.

In one embodiment of the bilayer composition, the composition whereinthe one or more soluble calcium phosphate remineralizing agents arepresent only in the rapidly disintegrating layer.

The present application provides a method of treating a subjectsuffering from xerostomia which comprises administering to the subject,in an amount effective to treat the xerostomia, a bilayer composition ofthe present application.

In one embodiment, the method wherein the bilayer composition furtherwhitens teeth in the subject's mouth.

In one embodiment, an oral care composition comprising:

-   -   a) a whitening agent;    -   and one or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes; and    -   d) one or more soluble calcium phosphate remineralizing agents.

In one embodiment, an oral care composition comprising:

-   -   a) emu oil;    -   and one or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes; and    -   d) one or more soluble calcium phosphate remineralizing agents.

In one embodiment, an oral care composition consisting essentially of:

-   -   a) a whitening agent;    -   and one or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes; and    -   d) one or more soluble calcium phosphate remineralizing agents.

In one embodiment, an oral care composition consisting essentially of:

-   -   a) emu oil; and one or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes; and    -   d) one or more soluble calcium phosphate remineralizing agents.

The present application provides a package comprising:

-   -   i) a first oral care composition comprising:        -   a) a whitening agent;        -   and one or more of the following:        -   b) one or more emulsifying agents;        -   c) one or more protease enzymes; and        -   d) one or more soluble calcium phosphate remineralizing            agents;    -   ii) a second oral care composition comprising        -   a) emu oil;        -   and one or more of the following:        -   b) one or more emulsifying agents;        -   c) one or more protease enzymes; and        -   d) one or more soluble calcium phosphate remineralizing            agents; and    -   iii) instruction for use of the first oral care composition and        second oral care composition to treat a subject afflicted with        mucositis or xerostomia.

The present application provides a package consisting essentially of:

-   -   i) a first oral care composition comprising:        -   a) a whitening agent;        -   and one or more of the following:        -   b) one or more emulsifying agents;        -   c) one or more protease enzymes; and        -   d) one or more soluble calcium phosphate remineralizing            agents;    -   ii) a second oral care composition comprising:        -   a) emu oil;        -   and one or more of the following:        -   b) one or more emulsifying agents;        -   c) one or more protease enzymes; and        -   d) one or more soluble calcium phosphate remineralizing            agents; and    -   iii) instruction for use of the first oral care composition and        second oral care composition to treat a subject afflicted with        mucositis or xerostomia.

The present application provides a therapeutic package for dispensingto, or for use in dispensing to, a subject afflicted with mucositis orxerostomia, which comprises:

-   -   i) a first oral care composition comprising:        -   a) a whitening agent;        -   and one or more of the following:        -   b) one or more emulsifying agents;        -   c) one or more protease enzymes; and        -   d) one or more soluble calcium phosphate remineralizing            agents;    -   ii) a second oral care composition comprising:        -   a) emu oil;        -   and one or more of the following:        -   b) one or more emulsifying agents;        -   c) one or more protease enzymes; and        -   d) one or more soluble calcium phosphate remineralizing            agents; and    -   iii) labeling directing the use of said package in the treatment        of said subject.

The present application provides a therapeutic package for dispensingto, or for use in dispensing to, a subject afflicted with mucositis orxerostomia, which consists essentially of:

-   -   i) a first oral care composition comprising:        -   a) a whitening agent;        -   and one or more of the following:        -   b) one or more emulsifying agents;        -   c) one or more protease enzymes; and        -   d) one or more soluble calcium phosphate remineralizing            agents;    -   ii) a second oral care composition comprising:        -   a) emu oil;        -   and one or more of the following:        -   b) one or more emulsifying agents;        -   c) one or more protease enzymes; and        -   d) one or more soluble calcium phosphate remineralizing            agents; and    -   iii) labeling directing the use of said package in the treatment        of said subject.

The present application provides a method of treating a subjectafflicted with mucositis or xerostomia comprising administering a firstoral care composition followed by one or more of a second oral carecomposition.

The present application provides a method treating a subject afflictedwith mucositis or xerostomia consisting essentially of administering afirst oral care composition followed by one or more of a second oralcare composition.

The present application provides a method treating a subject afflictedwith mucositis or xerostomia comprising administering a single firstoral care composition followed by five of a second oral carecomposition.

The present application provides a method treating a subject afflictedwith mucositis or xerostomia consisting essentially of administering asingle first oral care composition followed by five of a second oralcare composition.

In one embodiment, the first oral care composition comprises:

-   -   a) a whitening agent;    -   and one or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes; and    -   d) one or more soluble calcium phosphate remineralizing agents;        and        the second oral care composition comprises:    -   a) emu oil;    -   and one or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes; and    -   d) one or more soluble calcium phosphate remineralizing agents.

In one embodiment, the first oral care composition consists essentiallyof:

-   -   a) a whitening agent;    -   and one or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes; and    -   d) one or more soluble calcium phosphate remineralizing agents;        and        the second oral care composition consists essentially of:    -   a) emu oil;    -   and one or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes; and    -   d) one or more soluble calcium phosphate remineralizing agents.

In one embodiment the first oral care composition and the one or more ofa second oral care compositions are administering over 24 hours.

In one embodiment, the package is a sealed package.

In one embodiment, the sealed package is a blister pack.

In one embodiment, the blister pack contains one of the first oral carecomposition and five of the second oral care composition.

In one embodiment, the first oral care composition further comprisesisomalt.

In one embodiment, the first oral care composition further comprisessucrolose.

In one embodiment, the second oral care composition further comprisespotassium nitrate.

In one embodiment, the first oral care composition is a tablet. In oneembodiment, the tablet is an 800 mg tablet. In one embodiment, thetablet is a 1000 mg tablet.

In one embodiment, the second oral care composition is a tablet. In oneembodiment, the tablet is an 800 mg tablet. In one embodiment, thetablet is a 1000 mg tablet.

In one embodiment, the whitening agent is carbamide peroxide. In oneembodiment, the amount of carbamide peroxide in the tablet is 1 mg-5 mg.In one embodiment, the amount of carbamide peroxide in the tablet is 1mg-4 mg. In one embodiment, the amount of carbamide peroxide in thetablet is 2 mg-3 mg. In one embodiment, the amount of carbamide peroxidein the tablet is 1 mg. In one embodiment, the amount of carbamideperoxide in the tablet is 2 mg. In one embodiment, the amount ofcarbamide peroxide in the tablet is 2.5 mg.

In one embodiment, the emulsifying agent is soy lecithin. In oneembodiment, the concentration of the soy lecithin is between 1 to 5% byweight. In one embodiment, the concentration of the soy lecithin isbetween 2 to 5% by weight.

In one embodiment, the soluble calcium phosphate remineralizing agent istricalcium phosphate. In one embodiment, the concentration of thetricalcium phosphate is between 1 to 10% by weight. In one embodiment,the concentration of the tricalcium phosphate is between 3 to 10% byweight. In one embodiment, the concentration of the tricalcium phosphateis 10% by weight.

In one embodiment, the concentration of the emu oil is between 5 to

-   10% by weight. In one embodiment, the concentration of the emu oil    is between 5 to 7% by weight. In one embodiment, the concentration    of the emu oil is 6% by weight.

In one embodiment, the protease enzyme is stem bromelain. In oneembodiment, the amount of stem bromelain in the tablet is 25 mg-75 mg.In one embodiment, the amount of stem bromelain in the tablet is 40mg-60 mg. In one embodiment, the amount of stem bromelain in the tabletis 50 mg.

The present application provides an oral care composition comprising:

-   -   a) one or more omega fatty acids;    -   and one or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents;    -   e) one or more whitening agents.

In one embodiment, the composition comprising:

-   -   a) one or more omega fatty acids;    -   and two or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents;    -   e) one or more whitening agents.

In one embodiment, the composition comprising:

-   -   a) one or more omega fatty acids;    -   and three or more of the following:    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents;    -   e) one or more whitening agents.

In one embodiment, the composition comprising each of the following:

-   -   a) one or more omega fatty acids;    -   b) one or more emulsifying agents;    -   c) one or more protease enzymes;    -   d) one or more soluble calcium phosphate remineralizing agents;    -   e) one or more whitening agents.

In one embodiment, the composition wherein the one or more omega fattyacids comprise omega-3 fatty acids or omega-6 fatty acids.

In one embodiment, the composition wherein the omega-3 fatty acid isalpha-linoleic acid and the omega-6 fatty acid is gamma-linoleic acid.

In one embodiment, a composition for treating xerostomia. In oneembodiment, a composition for treating dry mouth. In one embodiment, acomposition for treating mucositis.

In some embodiments of the present methods, the mucositis is mucositisof the oral cavity and pharynx. In some embodiments of the presentmethods, the xerostomia is xerostomia of the oral cavity and pharynx.

In one embodiment, a composition for whitening teeth.

In one embodiment, a composition for remineralizing teeth.

In one embodiment, a composition for whitening and remineralizing teeth.

In one embodiment, the composition has a cariostatic effect on thesubject's teeth. In one embodiment, the composition has ananti-cariogenic effect on the subject's teeth.

In one embodiment, the concentration of emu oil in the composition isbetween 0.1 to 60% by weight.

In one embodiment, the concentration of peroxide in the composition isbetween 0.1 to 50% by weight. Concentration of peroxide in excess of 40%by weight would be for professional use.

In one embodiment, the concentration of soluble calcium phosphate in thecomposition is between 0.1 to 50% by weight.

In one embodiment, the concentration of the protease enzyme in thecomposition is between 0.1 to 40% by weight.

In one embodiment, the concentration of the phospholipids in thecomposition is between 0.1 to 20% by weight.

In one embodiment, the concentration of emu oil in the slowly erodinglayer is between 0.1 to 15% by weight. In one embodiment, theconcentration of emu oil in the slowly eroding layer is between 1.0 to10% by weight. In one embodiment, the concentration of emu oil in theslowly eroding layer is between 5 to 10% by weight. In one embodiment,the concentration of emu oil in the slowly eroding layer is 10% byweight.

In some embodiments, the whitening agent is an oxidizing agent.

Different oxidizing agent can be used in the composition. Examples ofoxidizing agent include, but are not limited to, peroxides. In someembodiments, the whitening agent is selected from the group comprisingof one or more of carbamide peroxide and hydrogen peroxide.

In one embodiment, the concentration of the peroxide in thedisintegrating layer is between 0.1 to 20% by weight. In one embodiment,the concentration of the peroxide in the disintegrating layer is between1.0 to 20% by weight. In one embodiment, the concentration of theperoxide in the disintegrating layer is between 1.0 to 10% by weight. Inone embodiment, the concentration of the peroxide in the disintegratinglayer is between 1.0 to 5% by weight. In one embodiment, theconcentration of the peroxide in the disintegrating layer is 1.0% byweight.

Different protease enzymes can be used in the composition. Examples ofproteases include, but are not limited to, the group comprising of oneor more of papain, trypsin, chymotrypsin, aminopeptidase,carboxypeptidase, pepsin, and cathepsin.

In one embodiment, papain is used. In one embodiment, the proteaseenzyme is obtained from a papaya extract.

In one embodiment, the concentration of the protease enzyme in the sloweroding layer is between 0.1% to 20% by weight. In one embodiment, theconcentration of the protease enzyme in the slow eroding layer isbetween 1% to 20% by weight. In one embodiment, the concentration of theprotease enzyme in the slow eroding layer is between 1% to 10% byweight. In one embodiment, the concentration of the protease enzyme inthe slow eroding layer is between 5% to 15% by weight. In oneembodiment, the concentration of the protease enzyme in the slow erodinglayer is 5% by weight. In one embodiment, the concentration of theprotease enzyme in the slow eroding layer is 10% by weight.

In one embodiment, the soluble calcium phosphate remineralizing agent isselected from the group comprising of one or more of dibasic calciumphosphate, monocalcium phosphate, dicalcium phosphate anhydrous,tricalcium phosphate, and tetracalcium phosphate. In one embodiment,tricalcium phosphate, dicalcium phosphate anhydrous, tetracalciumphosphate or dibasic calcium phosphate anhydrous are used. In oneembodiment, tricalcium phosphate is used.

In one embodiment, the concentration of the soluble calcium phosphateremineralizing agent in the disintegrating layer is between 0.1% to

-   50% by weight. In one embodiment, the concentration of the soluble    calcium phosphate remineralizing agent in the disintegrating layer    is between 1% to 25% by weight. In one embodiment, the concentration    of the soluble calcium phosphate remineralizing agent in the    disintegrating layer is between 5% to 25% by weight. In one    embodiment, the concentration of the soluble calcium phosphate    remineralizing agent in the disintegrating layer is between 9.5% to    20% by weight. In one embodiment, the concentration of the soluble    calcium phosphate remineralizing agent in the disintegrating layer    is 9.5% by weight. In one embodiment, the concentration of the    soluble calcium phosphate remineralizing agent in the disintegrating    layer is 20% by weight.

In one embodiment, the concentration of the soluble calcium phosphateremineralizing agent in the slowly eroding layer is between 0.1% to

-   50% by weight. In one embodiment, the concentration of the soluble    calcium phosphate remineralizing agent in the slowly eroding layer    is between 1% to 35% by weight. In one embodiment, the concentration    of the soluble calcium phosphate remineralizing agent in the slowly    eroding layer is between 10% to 35% by weight. In one embodiment,    the concentration of the soluble calcium phosphate remineralizing    agent in the slowly eroding layer is 10% by weight. In one    embodiment, the concentration of the soluble calcium phosphate    remineralizing agent in the slowly eroding layer is 35% by weight.

In one embodiment, the concentration of the phospholipids in the sloweroding layer is between 0.1% to 20% by weight. In one embodiment, theconcentration of the phospholipids in the slow eroding layer is between1% to 10% by weight. In one embodiment, the concentration of thephospholipids in the slow eroding layer is between 1% to 2% by weight.In one embodiment, the concentration of the phospholipids in the sloweroding layer is 2% by weight. In one embodiment, the concentration ofthe phospholipids in the slow eroding layer is 1% by weight.

In order for calcium phosphate to act as a remineralizing agent, it ispreferable that the calcium phosphate be in soluble form. If asignificant portion of the calcium phosphate were to precipitate out ofsolution, it would function as an abrasive agent and not as aremineralizer. The addition of glycerin to the composition acts to keepthe calcium phosphate from forming a precipitate.

In one embodiment, the composition further comprises glycerin. In oneembodiment, the concentration of glycerin is between 10 to 60% byweight.

In one embodiment, the composition further comprises fluoride, forexample sodium fluoride. In one embodiment, the concentration of sodiumfluoride is between 0.01 to 5% by weight.

In one embodiment, the remineralizing agent is white in color. Thus, theuptake of remineralizing material may contribute to the whiteningeffect.

In one embodiment, the composition contains potassium nitrate, which canact as a desensitizing agent.

The composition can be provided in a carrier. In different embodiments,the carrier is selected from the group consisting of a tablet, a bilayertablet, a multilayer tablet, a chewing gum, a candy, a toothpaste, alozenge, a powder, a gel, a viscous gel, an ointment, a cream, a liquid,a mouthwash, and a candy.

In one embodiment, the liquid carrier or mouthwash carrier furthercomprises sodium bicarbonate.

In some embodiments, the bilayer tablet comprises a disintegrating layerand a slowly eroding layer. The differing relative rates of release ofactive material content from the disintegrating layer and a slowlyeroding layer of the tablet may be achieved in various ways.

The differing rates of release may be achieved by a first layer which isa disintegrating layer which releases the bulk of its active materialcontent within a relatively short time, for example, including, but notlimited to, within 1 min, 10 min, 30 min, or 1 hour, and a second layerwhich is a slowly eroding layer which releases the bulk of its activematerial content during a relatively long period after administration orafter a period of delay after administration.

The disintegrating layer may have a composition similar to that of knownrapidly disintegrating tablets. Slowly eroding layers may have acomposition similar to that of known slowly eroding tablets and maycomprise active material content together with a release retardingmaterial.

In some embodiments, the composition is a single layer tablet comprisinga disintegrating fraction and a slowly eroding fraction. Thedisintegrating fraction may be intermingled uniformly or randomly withthe slowly eroding fraction. In some embodiments, the whitening agent isfound only in the disintegrating fraction.

In some embodiments, the composition is a bilayer layer tabletcomprising a slowly eroding tablet core and a disintegrating outerlayer. In some embodiments, the whitening agent is found only in thedisintegrating outer layer.

The advantages of the compositions disclosed herein include possiblesynergistic effects between the actions of the protease and thewhitening agent, and ease of use especially in a home or veterinarysetting. The compositions described in this patent disclosure arebelieved to provide improved effects both on extrinsic dental stains andon previously “untouchable” intrinsic dental stains. The removal ofchromogen from enamel is believed to be aided by the presence in thecomposition of a protease enzyme able to react with protein chromogensand the pellicle layer, creating enhanced mechanisms for penetration ofan oxygen free radical bleaching agent (e.g., hydrogen peroxidemolecules from carbamide peroxide solution or hydrogen peroxidesolution). It is believed that one of the effects of including proteaseswith whitening agents in accordance with this patent disclosure isdeeper penetration of the whitening agents into enamel, in addition tothe beneficial effect of the reaction of proteases with proteinchromogens.

The composition provides an advantageous ease of use in that it allowsfor treatment of xerostomia and a whitening agent, a protease enzyme,and a remineralizing agent to be applied to teeth using only a singlecomposition rather than having to apply the different components inseparate compositions. This is particularly advantageous for home andveterinary use, and when the composition is supplied in certaincarriers, such as for example chewing gum, toothpaste, lozenge,mouthwash, and candy.

The composition has the further advantage that when availableapplication time is limited, the whitening agent, protease enzyme, andremineralizing agent can be simultaneously applied to the teeth for thefull duration of the application time. In contrast, for the same totalavailable treatment time, if the whitening agent, protease enzyme, andremineralizing agent were applied in separate compositions, the time ofapplication of each component would have to be reduced in order to keeptotal treatment time constant.

In one embodiment of the composition, silica is added to the compositionto increase the viscosity of the composition. In other embodiments, thecomposition contains methylcellulose (10-20% by weight) or xantahan gum(10-20% by weight).

In some embodiments, a sweetener or flavorant can be added to thecomposition. In one embodiment, the concentration is between about0.2-10% by weight. In one embodiment the sweetener is saccharin oraspartame. In one embodiment the flavorant is peppermint or clove.

In some embodiments, the sweetener is maltitol, isomaltitol, manitol,lactitol, acesulfame potassium, cyclamate, taumatin or other knownsweeteners.

The pH of the composition can be adjusted. In one embodiment, the pH isbetween about pH 6 to 7.5. In one embodiment, baking soda is used as apH neutralizer.

Advantageous methods for whitening and remineralizing teeth are alsodisclosed. The methods comprise applying to teeth any of thecompositions described herein for whitening and remineralizing teeth.

In a further embodiment of any of the methods of whitening andremineralizing a subject's teeth described herein, a gel polymer is usedat the base of the teeth to contain the whitening and remineralizingcompositions to the teeth and to help avoid their contact with the gum.In different embodiments, the gel comprises polyethyl methylacrylate orpolymethyl methylacrylate with plastizers. A dental tray or dam can alsobe used for isolation of the dentition.

The total time for application of whitening and remineralizationcompositions can typically vary from 20-30 minutes to 2-3 hours. In ahome application setting, compositions can be applied to the teethovernight. In home application kits, the treatment time may vary between1-2 weeks to up to several weeks depending upon the stain. In oneembodiment, the whitening and remineralizing composition includes alight activated photo-initiator as an indicator of time exposure.

The compositions, kits and methods described herein can be used both onnatural teeth and on some types of artificial teeth.

Using the compositions, kits and methods described herein, loss ofcalcium that may occur during dental bleaching can be restored byremineralization so that a more efficacious whitening composition can beused safely with enhanced effect.

Advantageous methods for treating dental sensitivity and for treatingdental caries are also described herein and comprise applying any of thecompositions described herein to the subject's teeth. Bleaching cancause dental sensitivity. This sensitivity can be treated using thedescribed compositions, kits and methods for tooth whitening andremineralization. In addition, the described compositions, kits, andmethods can be used to treat dental sensitivity that occurs in theabsence of bleaching. Remineralization may decrease sensitivity bydecreasing the permeability of dentin. In addition, the describedcompositions, kits and methods for tooth whitening and remineralizationcan be used in other applications where remineralization would bebeneficial, for example in the treatment of dental caries.

After the whitening and remineralizing procedures described herein havebeen carried out, additional compositions for restorative or cosmeticpurposes may be applied to the teeth.

As used herein, “treating” means preventing, slowing, halting, orreversing the progression of a condition, disease or infection. Treatingmay also mean improving one or more symptoms of a condition, disease orinfection.

The compositions used in the method disclosed in this patentspecification may be administered in various forms, including thosedetailed herein. The treatment with the compositions may be a componentof a combination therapy or an adjunct therapy, i.e. the subject orpatient in need of the composition is treated or given another drug orcomposition for the condition, disease or infection in conjunction withone or more of the instant compositions. This combination therapy can besequential therapy where the patient is treated first with onecomposition or drug and then the other or the two are givensimultaneously. These can be administered independently by the sameroute or by two or more different routes of administration depending onthe dosage forms employed.

As used herein, a “pharmaceutically acceptable carrier” is apharmaceutically acceptable solvent, suspending agent or vehicle, fordelivering the instant compositions to the animal or human. The carriermay be liquid or solid and is selected with the planned manner ofadministration in mind. Liposomes are also a pharmaceutically acceptablecarrier.

The dosage of the compositions administered in treatment will varydepending upon factors such as the pharmacodynamic characteristics ofthe compositions and its mode and route of administration; the age, sex,metabolic rate, absorptive efficiency, health and weight of therecipient; the nature and extent of the symptoms; the kind of concurrenttreatment being administered; the frequency of treatment with; and thedesired therapeutic effect.

A dosage unit of the composition used in the method of the presentinvention may comprise a single composition or mixtures thereof withadditional agents. The compounds can be administered in oral dosageforms as tablets, capsules, pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions.

The compositions used in the method of the present invention can beadministered in admixture with suitable pharmaceutical diluents,extenders, excipients, or carriers (collectively referred to herein as apharmaceutically acceptable carrier) suitably selected with respect tothe intended form of administration and as consistent with conventionalpharmaceutical practices.

The compositions can be administered alone or mixed with apharmaceutically acceptable carrier. This carrier can be a solid orliquid, and the type of carrier is generally chosen based on the type ofadministration being used.

Techniques and compositions for making dosage forms useful in thepresent invention are described in the following references: 7 ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel,Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976);Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company,Easton, Pa., 1985); Advances in Pharmaceutical Sciences (DavidGanderton, Trevor Jones, Eds., 1992); Advances in PharmaceuticalSciences Vol. 7. (David Ganderton, Trevor Jones, James McGinity, Eds.,1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugsand the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs andthe Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); DrugDelivery to the Gastrointestinal Tract (Ellis Horwood Books in theBiological Sciences. Series in Pharmaceutical Technology; J. G. Hardy,S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and thePharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T.Rhodes, Eds.). All of the aforementioned publications are incorporatedby reference herein.

Tablets may contain suitable binders, lubricants, disintegrating agents,coloring agents, flavoring agents, flow-inducing agents, and meltingagents. For instance, for oral administration in the dosage unit form ofa tablet or capsule, the active drug component can be combined with anoral, non-toxic, pharmaceutically acceptable, inert carrier such aslactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose,magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol,sorbitol and the like. Suitable binders include starch, gelatin, naturalsugars such as glucose or beta-lactose, corn sweeteners, natural andsynthetic gums such as acacia, tragacanth, or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

In the present application, all numbers or percentages disclosed hereinare approximate values, regardless whether the word “about” or“approximate” is used in connection therewith. They may vary by 1percent, 2 percent, 5 percent, or up to 20 percent. Whenever a numericalrange with a lower limit and an upper limit is disclosed, any numberfalling within the range is specifically disclosed.

Each embodiment disclosed herein is contemplated as being applicable toeach of the other disclosed embodiments. Thus, all combinations of thevarious elements described herein are within the scope of the invention.

This patent specification will be better understood by reference to theExperimental Details which follow, but those skilled in the art willreadily appreciate that the specific experiments detailed are onlyillustrative of the invention as described more fully in the claimswhich follow thereafter.

Experimental Details Materials and Methods

When possible, compendial (e.g, USP) grades or phannaceutical grades ofthe chemicals were obtained. Carbamide peroxide is an oxidizing agentgenerally used for its oxygen-releasing effect in the local treatmentand hygienic prevention of minor infections and inflammation orirritation of the gums and mouth, including canker sores (aphthousulcers), gingivitis, periodontitis, stomatitis, and Vincent's infection.The drug also is used in the treatment of minor inflammation caused bydentures, mouth appliances (orthodontics), or dental procedures. Thematerial obtained here is a white, crystalline powder with a relativelylarge particle size.

Omega fatty acids include omega-3 fatty acid, omega-6 fatty acid andomega-9 fatty acids. Omega-3 fatty acids are a family of unsaturatedfatty acids that have in common a final carbon-carbon double bond in then-3 position, that is, the third bond, counting from the methyl end.Omega-6 fatty acids are a family of unsaturated fatty acids that have incommon a final carbon-carbon double bond in the n-6 position, that is,the sixth bond, counting from the methyl end. Omega-9 fatty acids are afamily of unsaturated fatty acids that have in common a finalcarbon-carbon double bond in the n-9 position, that is, the ninth bond,counting from the methyl end.

Omega-3 fatty acids include but are not limited to Hexadecatrienoic acid(HTA), alpha-Linolenic acid (ALA), Stearidonic acid (SDA).Eicosatrienoic acid (ETE), Eicosatetraenoic acid (ETA), Eicosapentaenoicacid (EPA), Heneicosapentaenoic acid (HPA), Docosapentaenoic acid (DPA),Clupanodonic acid, Docosahexaenoic acid (DHA), Tetracosapentaenoic acidor Tetracosahexaenoic acid.

Omega-6 fatty acids include but are not limited to Gamma-linolenic acid(GLA), Calendic acid, Eicosadienoic acid, Dihomo-gamma-linolenic acid(DGLA), Arachidonic acid (AA), Docosadienoic acid, Adrenic acid,Docosapentaenoic acid, Tetracosatetraenoic acid, or Tetracosapentaenoicacid.

Omega-9 fatty acids include but are not limited to oleic acid, elaidicacid, gondoic acid, mead acid, erucic acid, nervonic acid.

Essential fatty acids cannot be synthesized by the human body and mustbe obtained from a dietary source. Because humans lack the requiredenzyme to introduce carbon-carbon double bonds at carbon atoms beyondthe ninth carbon atom in unsaturated fatty acids (the ninth carbon atomfrom the omega end of the chain). Gamma-linoleic acid (an ω-6 fattyacid) and alpha-linolenic acid (an ω-3 fatty acid) are essential fattyacids that must be obtained by humans from a dietary source to ensuregood wellness.

Non-limiting examples of suitable oil materials include oleic canola Oil(Brassica campestris, B. napus, B. rapa; characterized by having anoleic content greater than 70%, e.g., hi oleic canola oil, very higholeic canola oil, or partially hydrogenated canola oil), marula kerneloil (Sclerocarya birrea), palm oil (Elaeis Guineensis Oil), palm olein,palm stearin, palm superolein, pecan oil, pumpkin seed oil, oleicsafflower oil (Carthamus Tinctorius; characterized by having an oleiccontent of greater than about 30% and omega-6 fatty acid content of lessthan about 50%, e.g., hi oleic safflower oil), sesame oil (Sesamumindicum, S. oreintale, soybean oil (Glycine max, e.g., hi oleic soybean,low linolenic soybean oil, partially hydrogenated), oleic sunflower oil(Helianthus annus; characterized by having an oleic content of greaterthan about 40%, e.g., mid oleic sunflower or high oleic sunflower oil),and mixtures thereof. Oleic canola oil, palm oil, sesame oil, hi oleicsafflower oil, hi oleic soybean oil, mid oleic sunflower oil, and higholeic sunflower oil are common plant-bred derived oils and may be alsobe derived from non-genetically modified organisms (non-GMO).

The above oils are commercially-available from a number of vendors.

Emu oil is oil rendered from the fat of the emu, a bird indigenous toAustralia. Unadulterated emu oil can vary widely in color and viscosity,but is generally a yellow liquid composed of approximately

-   70% unsaturated fatty acids. The largest component is oleic acid, a    mono-unsaturated omega-9 fatty acid. Emu oil also contains roughly-   20% linoleic acid (omega-6 fatty acid) and 1-2% linolenic acid    (omega-3 fatty acid). Emu oil is marketed and promoted as a dietary    supplement with a wide variety of claimed health benefits.    Commercial emu oil supplements are not standardized and vary widely    in their potency. The Emu Oil used herein is marketed as Pro-Emu Oil    from Progressive Emu Inc., PO Box 590088, Birmingham, Ala. 35259 and    is a formulated product which includes some vitamin E.

Emu oil is oil rendered from the fat of the emu, a bird indigenous toAustralia. Unadulterated emu oil can vary widely in color and viscosity,but is generally a yellow liquid composed of approximately

-   70% unsaturated fatty acids. The largest component is oleic acid, a    mono-unsaturated omega-9 fatty acid. Emu oil also contains roughly-   20% linoleic acid (an omega-6 fatty acid) and 1-2% linolenic acid    (an omega-3 fatty acid). Emu oil is marketed and promoted as a    dietary supplement with a wide variety of claimed health benefits.    Commercial emu oil supplements are not standardized and vary widely    in their potency. The Emu Oil used herein is marketed as Pro-Emu Oil    from Progressive Emu Inc., PO Box 590088, Birmingham, Ala. 35259 and    is a formulated product which includes some vitamin E.

Lecithins vary greatly in their physical form, from viscous semi-liquidsto powders, depending upon the free fatty acid content. They may alsovary in color from brown to light yellow, depending upon whether theyare bleached or unbleached or on the degree of purity. When they areexposed to air, rapid oxidation occurs, also resulting in a dark yellowor brown color. The Lecithin utilized herein is a brown to light yellowwax-like material that may be difficult to distribute throughout a solidpowder by traditional blending. It should be noted that Lecithin isincompatible with esterases owing to hydrolysis and it is alsoincompatible with oxidizing agents. Thus, the Lecithin should beseparated from the carbamide peroxide.

In addition to other pharmaceutical excipients, Agglomerated isomalt waschosen as “filler” for the tablet formulations. Specifically, galenIQ™720 (low solubility) and galenIQ™ 721 (high solubility) are agglomeratedspherical isomalts for direct compression applications. In general,these exipients are of non-animal origin, they have very lowhygroscopicity, grades with different solubilities are available, theyhave excellent chemical stability, and are highly resistant againstdegradation by enzymes and acids, they are generally regarded as anon-toxic, non-allergic and non-irritant material, and they have apleasant sugar-like, natural sweet taste profile. The higher solubilitygrade would be appropriate for a rapidly disintegrating layer, whereasthe low solubility grade would be appropriate for a slowly erodinglayer.

Papain is a white or grayish-white, slightly hygroscopic powder. Itspotency varies according to process of preparation with the usual gradedigesting −35 times its weight of lean meat. Papain is incompatible withstrong oxidizers and inactivated by oxidation. The papain used herein isdesignated as USP.

Example 1

The initial study (Table 1) focused on incorporation of the emu oil andlecithin into a solid dosage form (slow eroding tablet). Emu oil has afairly high melting point and the material employed here appears as afree flowing semi-solid at room temperature.

TABLE 1 Initial formulation for a slow eroding tablet layer containingoil, surfactant and re-mineralising agent. Actual Wt. % by Weight InWeight per per batch Item Component Blend tablet (mg) (g) 1 Isomalt(galen1Q 720) 80.9 202.4 7.1994 2 Anhydrous Dibasic Calcium 11.5 28.681.0202 Phosphate (Anhydrous Emcompress, JRS Pharma) 3 Emu Oil (Pro-EmuOil, Progressive 5.68 14.21 0.5054 Emu) 4 Lecithin NF (Spectrum) 1.914.764 0.1695 TOTAL 100.0 (approx.) 250.0 8.895

The following outcomes were obtained from this initial trial:

-   -   The powder mass accommodated the oil well; a very clean and dust        free mixture was obtained.    -   Distribution of the lecithin was non-uniform, and subsequent        processing efforts involve melting the lecithin and/or mixing it        with the Emu Oil to produce a liquid form before combining it        with powder.    -   The mixture compacted easily on a Carver Press to form strong        tablets. The oil appeared to reduce die wall friction        sufficiently to obviate the need for the addition of a        lubricant.    -   When placed in water, the tablet erodes slowly—complete erosion        occurred in approximately 5 minutes. During this time, the        liquid becomes cloudy, presumably due to emulsification of the        oil. The dicalcium phosphate appears as insoluble particles.    -   The tablet has a neutral taste; the Isomalt does not provide        noticeable sweetness nor does it provide the endothermic cooling        associated with a filler like sorbitol.

Procedure for preparation of composition described in Table 1:

-   1) Accurately weigh the Emu Oil (Item 3) into a disposable    polyethylene weighing dish.-   2) Accurately weigh the Isomalt (Item 1) into a disposable    polyethylene weighing dish.-   3) Take a portion of the Isomalt weighed in step 2 and transfer it    into the dish containing the Emu Oil. Use a spatula to mix the    powder with the oil. After mixing, transfer this mass to a glass    mortar. Repeat this procedure using additional portions of Isomalt    until all the Emu Oil has been absorbed onto powder. Transfer any    remaining Isomalt into the glass mortar.-   4) Accurately weigh the Anhydrous Dibasic Calcium Phosphate (item 2)    into a disposable polyethylene weighing dish, and transfer this    powder into the glass mortar containing the Isomalt and Emu Oil    mixture.-   5) Triturate the mixture in the mortar with a pestle to obtain a    uniform blend.-   6) Accurately weigh the Lecithin (Item 4) and transfer it to the    mixture in the mortar.-   7) Triturate the mixture in the mortar with a pestle to obtain a    uniform blend.-   8) Compress powder samples into tablets using a Carver press.

Example 2

A second, similar formulation was processed. Given the taste assessmentdescribed above, aspartame was included as a sweetener (Table 2). Interms of processing, in this case, the lecithin was added to Emu oil andthe mixture was warmed in a microwave oven to obtain a liquid mixture.This mixture was then added to the blend of isomalt and anhydrousdicalcium phosphate.

TABLE 2 Modified formulation for a slow eroding tablet layer containingoil, surfactant and remineralizing agent. % by Weight per Weight tabletActual Wt. Item Component In Blend (mg) per batch (g) 1 Isomalt (galen1Q720) 82.0 207.50 8.3000 2 Anhydrous Dibasic Calcium Phosphate 10.0 25.001.0000 (Anhydrous Emcompress, JRS Pharma) 3 Emu Oil (Pro-Emu Oil,Progressive 6.00 15.00 0.6000 Emu) 4 Lecithin NF (Spectrum) 1.00 2.500.1000 5 Aspartame (Equal, Merisant Co.) 1.00 2.50 0.1000 TOTAL 100.0252.5 10.144

Heating of the lecithin/Emu oil mixture was done by placing a beaker inthe microwave oven and heating for 30 second intervals. After eachinterval, the mixture was stirred. Fragments of the lecithin continuedto be present and a total of approximately 5 intervals was required; itappeared that the lecithin eventually melted and/or dissolved in theoil. It should be noted that in subsequent processing, heating forlonger time intervals led to apparent decomposition of the lecithin.

Tablets were produced from this blend and they had similar physicalattributes to those obtained previously. The addition of the aspartameproduced a slight improvement in taste, but additional sweetener couldbe required.

Procedure for preparation of composition described in Table 2:

-   1) Accurately weigh the Lecithin (Item 4) into a 50 mL glass beaker.-   2) Tare the beaker containing the Lecithin and accurately weigh the    Emu Oil (item 3) into the beaker containing the Lecithin.-   3) Accurately weigh the Anhydrous Dibasic Calcium Phosphate (Item 2)    into a disposable polyethylene weighing dish.-   4) Transfer the Anhydrous Dibasic Calcium Phosphate (Item 2) into a    glass mortar. Triturate until a fine powder is obtained.-   5) Accurately weigh the Isomalt (Item 1) into a disposable    polyethylene weighing dish. Transfer the Isomalt to the mortar    containing Anhydrous Dibasic Calcium Phosphate. Triturate to obtain    a uniform blend and then transfer the blend to a weighing dish.-   6) Place the beaker containing the lecithin and Emu Oil into the    microwave oven and heat until the Lecithin melts. Use a spatula to    mix the Lecithin with the oil.-   7) Take a portion of the powder mixture obtained from 5 and transfer    it into the beaker containing the Lecithin and Emu Oil mixture. Use    a spatula to mix the powder with the oil. After mixing, transfer    mass to a glass mortar. Repeat this procedure using additional    portions of powder mixture until all the Lecithin and Emu oil has    been absorbed onto powder. Transfer any remaining powder into the    glass mortar.-   8) Triturate the mixture in the mortar with a pestle to obtain a    uniform blend.-   9) Accurately weigh the Aspartame (Item 5) and transfer it to the    mixture in the mortar. Triturate to form a uniform mixture.-   10) Compress powder samples into tablets using a Carver Press.

Example 3

Presented in Table 3 is a bilayer tablet formulation. An initialformulation was developed for the rapidly disintegrating layer, builtaround the concept of using a directly compressible dicalcium phosphatecarrier and also including crospovidone, a so-called “super”disintegrant. Dicalcium phosphate seemed to be a good choice because itis inorganic and therefore not incompatible with the strong oxidizercarbamide peroxide. Also, the rapid disintegration would release asubstantial quantity of a re-mineralizing agent. Due to itsincompatibility with strong oxidizers, papain was included in the sloweroding layer, and the isomalt was replaced with sorbitol.

TABLE 3 Initial Bilayer Tablet Formulation. % by Weight Weight perActual Wt. per Item Component In Blend tablet (mg) batch (g)Disintegrating Layer 1 Carbamide Peroxide (Spectrum) 1.0 2.5 0.1018 2Anhydrous Dibasic Calcium Phosphate 94.5 236.3 9.508 (AnhydrousEmcompress, JRS Pharma) 3 Crospovidone 3.50 8.75 0.3529 4 MagnesiumStearate 1.00 2.5 0.1040 TOTAL 100.0 250 10.0666 Slow Eroding Layer 5Sorbitol 78.0 390.0 7.7701 6 Anhydrous Dibasic Calcium Phosphate 10.050.00 1.0565 (Anhydrous Emcompress, JRS Pharma) 7 Papain USP30 (Anhui)5.0 25.00 0.5664 8 Emu Oil (Pro-Emu Oil, Progressive 6.00 30.00 0.6488Emu) 9 Lecithin NF (Spectrum) 1.00 5.00 0.1399 TOTAL 100 500.00 10.1817

The following outcomes were obtained from this trial:

-   -   The sorbitol, which has a larger particle size than the isomalt,        did not accommodate the oil as well. The overall character of        the blend for the slow eroding layer was more “oily”.    -   Each individual blend compacted easily to form strong tablets,        as did the combination of materials for the bilayer tablet.    -   When placed in water, the disintegrating layer does indeed        disintegrate rapidly releasing insoluble dicalcium phosphate        particles.    -   The second layer erodes slowly.    -   The sorbitol did not produce an improvement in taste.

Procedure for preparation of composition described in Table 3:

Disintegrating Layer

-   1) Accurately weigh the Anhydrous Dibasic Calcium Phosphate (Item 2)    into a disposable polyethylene weighing dish.-   2) Accurately weigh the Carbamide Peroxide (Item 1) and transfer the    powder into a glass mortar.-   3) Geometrically add the Anhydrous Dibasic Calcium Phosphate into a    glass mortar with trituration after each addition to produce a    uniform blend.-   4) Accurately weigh the Crospovidone (Item 3) and add it to the    powder blend in the glass mortar. Triturate to form a uniform blend.-   5) Accurately weigh the Magnesium Stearate (Item 4) and add it to    the powder blend in the glass mortal. Triturate lightly to form a    uniform blend.-   6) Transfer the blend into a bulk container and hold for tableting.

Slow Eroding Layer

-   7) Accurately weigh the Lecithin (Item 9) into a 50 mL glass beaker.-   8) Tare the beaker containing the lecithin and accurately weigh the    Emu Oil (Item 8) into the beaker containing the Lecithin.-   9) Accurately weigh the Anhydrous Dibasic Calcium Phosphate (Item 6)    into a disposable polyethylene weighing dish.-   10) Transfer the Anhydrous Dibasic Calcium Phosphate (item 6) into a    glass mortar. Triturate until a fine powder is obtained,-   11) Accurately weigh the Sorbitol (Item 5) into a disposable    polyethylene weighing dish, Transfer the Sorbitol to the mortar    containing the Anhydrous Dibasic Calcium Phosphate. Triturate to    obtain a uniform blend and then transfer the blend to a weighing    dish.-   12) Place the beaker containing the Lecithin and Emu Oil into the    microwave oven and heat until the Lecithin melts, Use a spatula to    mix the Lecithin with the oil.-   13) Take a portion of the powder mixture obtained from step 1 and    transfer it into the beaker containing the Lecithin and Emu Oil    mixture. Use a spatula to mix the powder with the oil. After mixing,    transfer this mass to a glass mortar. Repeat this procedure using    additional portions of powder mixture until all the Lecithin and Emu    Oil has been absorbed onto powder. Transfer any remaining powder    into the glass mortar.-   14) Triturate the mixture in the mortar with a pestle to obtain a    uniform blend.-   15) Accurately weigh the Papain (Item 7) and add it into a glass    mortar. Triturate until a uniform mixture is obtained.-   16) Transfer the blend into a bulk container and hold for tableting.

Bilayer Tablet Production

-   17) Weigh approximately 500 mg of the powder for the slow eroding    layer and transfer it into the die, Compress the powder into the    first layer using a Carver Press.-   18) Weigh approximately 250 mg of the powder for the disintegrating    layer and transfer it into the die containing the first layer.    Compress the powder onto the first layer using the Carver press.-   19) Eject tablet from die.

Example 4

Modifications made in the next iteration (Table 4) include a replacementof the sorbitol with isomalt, and the use of relatively large,capsule-shaped tablet tooling. A tablet size of 1.2 g was targeted, with400 mg and 800 mg for the disintegrating and eroding layers,respectively.

TABLE 4 Carbamide Peroxide (4 mg) and Papain (40 mg) bilayer tabletformulation. % by Weight per Weight In tablet Actual Wt. per ItemComponent Blend (mg) batch (g) Disintegrating Layer 1 Carbamide Peroxide(Spectrum) 1.0 4.00 0.1107 2 Anhydrous Dibasic Calcium Phosphate 94.5378.00 9.479 (Anhydrous Emcompress, JRS Pharma) 3 Crospovidone 3.5014.00 0.3601 4 Magnesium Stearate 1.00 4.00 0.1053 TOTAL 100.0 400.010.0551 Slow Eroding Layer 5 Isomalt 78.0 624.0 7.7967 6 AnhydrousDibasic Calcium Phosphate 10.0 80.0 1.0722 (Anhydrous Emcompress, JRSPharma) 7 Papain USP30 (Anhui) 5.0 40.0 0.5243 8 Emu Oil (Pro-Emu Oil,Progressive 6.00 48.0 0.6330 Emu) 9 Lecithin NF (Spectrum) 1.00 8.00.1008 TOTAL 100.0 800.0 10.127

Subsequent to manufacture of these bilayer tablets, two things becameevident. When handling this tablet, it appeared that the edges of thislayer were easily abraded. Second, when placed in simulated intestinalfluid, a large quantity of insoluble dicalcium phosphate was released,which might be “gritty” and not be desirable.

Procedure for preparation of composition described in Table 4:

Disintegrating Layer

-   1) Accurately weigh the Anhydrous Dibasic Calcium Phosphate (Item 2)    into a disposable polyethylene weighing dish.-   2) Accurately weigh the Carbamide Peroxide (Item 1) and transfer the    powder into a glass mortar.-   3) Geometrically add the Anhydrous Dibasic Calcium Phosphate into a    glass mortar with trituration after each addition to produce a    uniform blend.-   4) Accurately weigh the Crospovidone (Item 3) and add it to the    powder blend in the glass mortar. Triturate to form a uniform blend.-   5) Accurately weigh the Magnesium Stearate (Item 4) and add it to    the powder blend in the glass mortal. Triturate lightly to form a    uniform blend.-   6) Transfer the blend into a bulk container and hold for tableting.

Slow Eroding Layer

-   7) Accurately weigh the Lecithin (Item 9) into a 50 mL glass beaker.-   8) Tare the beaker containing the lecithin and accurately weigh the    Emu Oil (Item 8) into the beaker containing the Lecithin.-   9) Accurately weigh the Anhydrous Dibasic Calcium Phosphate (Item 6)    into a disposable polyethylene weighing dish.-   10) Transfer the Anhydrous Dibasic Calcium Phosphate (item 6) into a    glass mortar. Triturate until a fine powder is obtained.-   11) Accurately weigh the Isomalt (Item 5) into a disposable    polyethylene weighing dish. Transfer the Isomalt to the mortar    containing the Anhydrous Dibasic Calcium Phosphate. Triturate to    obtain a uniform blend and then transfer the blend to a weighing    dish.-   12) Place the beaker containing the Lecithin and Emu Oil into the    microwave oven and heat until the Lecithin melts, Use a spatula to    mix the Lecithin with the oil.-   13) Take a portion of the powder mixture obtained from step 11 and    transfer it into the beaker containing the Lecithin and Emu Oil    mixture. Use a spatula to mix the powder with the oil. After mixing,    transfer this mass to a glass mortar. Repeat this procedure using    additional portions of powder mixture until all the Lecithin and Emu    Oil has been absorbed onto powder. Transfer any remaining powder    into the glass mortar.-   14) Triturate the mixture in the mortar with a pestle to obtain a    uniform blend.-   15) Accurately weigh the Papain (Item 7) and add it into a glass    mortar. Triturate until a uniform mixture is obtained.-   16) Transfer the blend into a bulk container and hold for tableting.

Bilayer Tablet Production

-   17) Weigh approximately 650 mg of the powder for the slow eroding    layer and transfer it into the die, Compress the powder into the    first layer using a Carver Press.-   18) Weigh approximately 350 mg of the powder for the disintegrating    layer and transfer it into the die containing the first layer.    Compress the powder onto the first layer using the Carver press.-   19) Eject tablet from die.

Example 5

A reduction in the quantity of phosphate salt was made and a solublefiller was added. Thus, in the next iteration (Table 5) theconcentration of dicalcium phosphate was reduced and isomalt wasincluded as the soluble filler in the disintegrating layer. The bilayertablet produced from the formulation in Table 5 showed no signs ofincompatibility in the dosage form. There is considerable flexibility inthe tablet in terms of both composition, weight, and the weight of therespective layers.

TABLE 5 Modified Carbamide Peroxide (4 mg) and papain (40 mg) bilayertablet formulation. % by Weight Weight per Actual Wt. per Item ComponentIn Blend tablet (mg) batch (g) Disintegrating Layer 1 Carbamide Peroxide(Spectrum) 1.0 4.00 0.1042 2 Anhydrous Dibasic Calcium Phosphate 9.538.00 0.969 (Anhydrous Emcompress, JRS Pharma) 3 Isomalt (galenIQ 720)85.0 340.00 8.519 4 Crospovidone 3.5 14.00 0.3488 5 Magnesium Stearate1.00 4.00 0.1087 TOTAL 100.0 400.0 10.0497 Slow Eroding Layer 6 Isomalt(galenIQ 720) 78.0 624.0 7.8036 7 Anhydrous Dibasic Calcium Phosphate10.0 80.0 1.406 (Anhydrous Emcompress, JRS Pharma) 8 Papain USP30(Anhui) 5.0 40.0 0.5454 9 Emu Oil (Pro-Emu Oil, Progressive 6.00 48.00.6929 Emu) 10 Lecithin NF (Spectrum) 1.00 8.0 0.1100 TOTAL 100.0 800.010.1925

Procedure for preparation of composition described in Table 5:

Disintegrating Layer

-   1) Accurately weigh the Anhydrous Dibasic Calcium Phosphate (Item 2)    into a disposable polyethylene weighing dish.-   2) Accurately weigh the Carbamide Peroxide (Item 1) and transfer the    powder into a glass mortar.-   3) Add the Anhydrous Dibasic Calcium Phosphate into the glass mortar    and triturate to produce a uniform blend.-   4) Accurately weigh the Isomalt (Item 3) and add it to the powder    blend in the glass mortar. Triturate to form a uniform blend.-   5) Accurately weigh the Crospovidone (Item 4) and the Magnesium    Stearate (Item 5) and add them to the powder blend in the glass    mortar. Triturate lightly to form a uniform blend.-   6) Transfer the blend into a bulk container and hold for tableting.

Slow Eroding Layer

-   7) Accurately weigh the Lecithin (Item 10) into a 50 mL glass    beaker.-   8) Tare the beaker containing the lecithin and accurately weigh the    Emu Oil (Item 9) into the beaker containing the Lecithin.-   9) Accurately weigh the Anhydrous Dibasic Calcium Phosphate (Item 6)    into a disposable polyethylene weighing dish.-   10) Transfer the Anhydrous Dibasic Calcium Phosphate (Item 7) into a    glass mortar. Triturate until a fine powder is obtained.-   11) Accurately weigh the Isomalt (Item 6) into a disposable    polyethylene weighing dish. Transfer the Isomalt to the mortar    containing the Anhydrous Dibasic Calcium Phosphate. Triturate to    obtain a uniform blend and then transfer the blend to a weighing    dish.-   12) Place the beaker containing the Lecithin and Emu Oil into the    microwave oven and heat until the Lecithin melts. Use a spatula to    mix the Lecithin with the oil.-   13) Take a portion of the powder mixture obtained from step 11 and    transfer it into the beaker containing the Lecithin and Emu Oil    mixture. Use a spatula to mix the powder with the oil. After mixing,    transfer this mass to a glass mortar. Repeat this procedure using    additional portions of powder mixture until all the Lecithin and Emu    Oil has been absorbed onto powder. Transfer any remaining powder    into the glass mortar.-   14) Triturate the mixture in the mortar with a pestle to obtain a    uniform blend.-   15) Accurately weigh the Papain (Item 8) and add it into a glass    mortar. Triturate until a uniform mixture is obtained.-   16) Transfer the blend into a bulk container and hold for tableting.

Bilayer Tablet Production

-   17) Weigh approximately 800 mg of the powder for the slow eroding    layer and transfer it into the die, Compress the powder into the    first layer using a Carver Press.-   18) Weigh approximately 400 mg of the powder for the disintegrating    layer and transfer it into the die containing the first layer.    Compress the powder onto the first layer using the Carver press.-   19) Eject tablet from die.

Example 6

Presented in FIG. 7 is another formulation. Several changes were madeincluding: 1) the weight of the rapidly disintegrating layer was reducedand that of the slowly eroding layer increased—there is no need for muchmass to accommodate the carbamide peroxide, and the larger the mass ofthe slowly eroding layer the more oil can be included; 2) Emu oil levelwas increased to 10% and lecithin level was increased from 1% to 2%.

The Emu oil and lecithin were combined in a beaker and heated on a hotplate with stirring. The temperature required to “melt” the lecithin andincorporate it into the oil was quite high. While it is possible toobtain what appears to be a one phase solution of the two components,excessive heating may change the character of the oil and/or degrade thelecithin.

TABLE 6 Modified Carbamide Peroxide (2 mg) and papain (100 mg) bilayertablet formulation including tricalcium phosphate. % by Weight Weightper Actual Wt. per Item Component In Blend tablet (mg) batch (g)Disintegrating Layer 1 Carbamide Peroxide (Spectrum) 1.0 2.00 0.2185 2Tricalcium Phosphate, Powder NF 20.0 40.00 3.995 3 Isomalt (galenIQ 720)73.0 146.00 14.605 4 Crospovidone 4.00 8.00 0.8164 5 Magnesium Stearate2.00 4.00 0.3880 TOTAL 100.0 200.0 20.0229 Slow Eroding Layer 6 Isomalt(galenIQ 720) 43.0 430.0 8.5481 7 Tricalcium Phosphate, Powder NF 35.0350.0 7.0121 8 Papain USP30 (Anhui) 10.0 100.0 2.0847 9 Emu Oil (Pro-EmuOil, 10.0 100.0 2.0679 Progressive Emu) 10 Lecithin NF (Spectrum) 2.0020.0 0.4002 TOTAL 100.0 1000.0 20.1130

The warm oily solution was added to the tricalcium phosphate with theexpectation that it could be distributed uniformly throughout thispowder. The combination of the fine powder and the decrease intemperature resulted in the formation of wax-like aggregates which werevery hard to completely disperse. After compression, there were yellowspots on the tablet surface that indicated that the distribution of theLecithin was not uniform. The mixture of the oil, lecithin, and powdersmay need to be heated to obtain the desired uniformity. In terms oflarger scale production this can be accomplished in a jacketed highshear mixer. It appeared that more oil could be accommodated and theconsistency of the slow eroding layer appears to be fine.

Procedure for preparation of composition described in Table 6:

Disintegrating Layer

-   1) Accurately weigh the Tricalcium Phosphate (Item 2) into a    disposable polyethylene weighing dish.-   2) Accurately weigh the Carbamide Peroxide (Item 1) and transfer the    powder into a glass mortar.-   3) Add the Tricalcium Phosphate into the glass mortar and triturate    to produce a uniform blend.-   4) Accurately weigh the Isomalt (Item 3) and add it to the powder    blend in the glass mortar. Triturate to form a uniform blend.-   5) Accurately weigh the Crospovidone (Item 4) and the Magnesium    Stearate (Item 5) and add them to the powder blend in the glass    mortar.

Triturate lightly to form a uniform blend.

-   6) Transfer the blend into a bulk container and hold for tableting.

Slow Eroding Layer

-   7) Accurately weigh the Lecithin (Item 10) into a 50 mL glass    beaker.-   8) Tare the beaker containing the lecithin and accurately weigh the    Emu Oil (Item 9) into the beaker containing the Lecithin.-   9) Accurately weigh the Tricalcium Phosphate (Item 7) into a    disposable polyethylene weighing dish.-   10) Accurately weigh the Isomalt (Item 6) into a disposable    polyethylene weighing dish.-   11) Place the beaker containing the Lecithin and Emu Oil on a hot    plate and heat until the Lecithin mixes with the oil.-   12) Add the tricalcium phosphate from step 9 into the beaker    containing the Lecithin and Emu Oil mixture. Use a spatula to mix    the powder with the oil. After mixing, transfer the mass to a glass    mortar. Repeat procedure using additional portions of the Isomalt    powder from step 10 and continue until all the Lecithin and Emu Oil    has been absorbed onto the powder. Transfer any remaining Isomalt    powder into the glass mortar.-   13) Triturate the mixture in the mortar with a pestle to obtain a    uniform blend.-   14) Accurately weigh the Papain (Item 8) and add it into a glass    mortar. Triturate until a uniform mixture is obtained.-   15) Transfer the blend into a bulk container and hold for tableting.

Bilayer Tablet Production

-   16) Weigh approximately 1000 mg of the powder for the slow eroding    layer and transfer it into the die, Compress the powder into the    first layer using a Carver Press.-   17) Weigh approximately 200 mg of the powder for the disintegrating    layer and transfer it into the die containing the first layer.    Compress the powder onto the first layer using the Carver press.-   18) Eject tablet from die.

Example 7

An attempt at increasing the oil level to 15% by weight is representedby the tablet described in Table 7. This batch was prepared at the 100 gsize with the expectation that it could be compressed on an instrumentedsingle station press to evaluate flow. However, when a screening studywas done on the Carver press, the rapidly disintegrating layer did notadhere to the slowly eroding layer. The applied pressure essentiallysqueezed the oil out of the carrier producing a highly lubricatedinterface between the layers.

TABLE 7 Modified Carbamide Peroxide (2 mg) and papain (100 mg) bilayertablet formulation including 15% emu oil. % by Weight Weight per ActualWt. per Item Component In Blend tablet (mg) batch (g) DisintegratingLayer 1 Carbamide Peroxide (Spectrum) 1.0 2.00 1.0385 2 TricalciumPhosphate, Powder NF 20.0 40.00 20.090 3 Isomalt (galenIQ 720) 73.0146.00 73.068 4 Crospovidone 4.00 8.00 3.9924 5 Magnesium Stearate 2.004.00 2.0100 TOTAL 100.0 200.0 100.1989 Slow Eroding Layer 6 Isomalt(galenIQ 720) 38.0 380.0 37.9956 7 Tricalcium Phosphate, Powder NF 35.0350.0 35.0067 8 Papain USP30 (Anhui) 10.0 100.0 10.0530 9 Emu Oil(Pro-Emu Oil, Progressive 15.00 150.0 15.1024 Emu) 10 Lecithin NF(Spectrum) 2.00 20.00 2.0863 TOTAL 100.0 1000.0 100.244

Procedure for preparation of composition described in Table 7:

Disintegrating Layer

-   1) Accurately weigh the Tricalcium Phosphate (Item 2) into a    disposable polyethylene weighing dish.-   2) Accurately weigh the Carbamide Peroxide (Item 1) and transfer the    powder into a glass mortar.-   3) Add the Tricalcium Phosphate into the glass mortar and triturate    to produce a uniform blend.-   4) Accurately weigh the Isomalt (Item 3) and add it to the powder    blend in the glass mortar. Triturate to form a uniform blend.-   5) Accurately weigh the Crospovidone (Item 4) and the Magnesium    Stearate (Item 5) and add them to the powder blend in the glass    mortar. Triturate lightly to form a uniform blend.-   6) Transfer the blend into a bulk container and hold for tableting.

Slow Eroding Layer

-   7) Accurately weigh the Lecithin (Item 10) into a glass beaker.-   8) Tare the beaker containing the lecithin and accurately weigh the    Emu Oil (Item 9) into the beaker containing the Lecithin.-   9) Accurately weigh the Tricalcium Phosphate (Item 7) into a    disposable polyethylene weighing dish.-   10) Accurately weigh the Isomalt (Item 6) into a disposable    polyethylene weighing dish.-   11) Place the beaker containing the Lecithin and Emu Oil on a hot    plate and heat until the Lecithin mixes with the oil.-   12) Add the tricalcium phosphate from step 9 into the beaker    containing the Lecithin and Emu Oil mixture. Use a spatula to mix    the powder with the oil. After mixing, transfer the mass to a glass    mortar. Repeat procedure using additional portions of the Isomalt    powder from step 10 and continue until all the Lecithin and Emu Oil    has been absorbed onto the powder. Transfer any remaining Isomalt    powder into the glass mortar.-   13) Triturate the mixture in the mortar with a pestle to obtain a    uniform blend.-   14) Accurately weigh the Papain (Item 8) and add it into a glass    mortar. Triturate until a uniform mixture is obtained.-   15) Transfer the blend into a bulk container and hold for tableting.

Bilayer Tablet Production

-   16) Weigh approximately 1000 mg of the powder for the slow eroding    layer and transfer it into the die, Compress the powder into the    first layer using a Carver Press.-   17) Weigh approximately 200 mg of the powder for the disintegrating    layer and transfer it into the die containing the first layer.    Compress the powder onto the first layer using the Carver press.-   18) Eject tablet from die.

Example 8

The following compositions are prepared using the methods describedhereinabove:

A composition comprising emu oil and one or more emulsifying agents. Acomposition comprising omega fatty acids and one or more emulsifyingagents. A composition comprising omega fatty acids and one or moreprotease enzymes. A composition comprising omega fatty acids and one ormore soluble calcium phosphate remineralizing agents. A compositioncomprising omega fatty acids and one or more whitening agents. Acomposition comprising omega fatty acids and two of the following: oneor more emulsifying agents, one or more protease enzymes, one or moresoluble calcium phosphate remineralizing agents, one or more whiteningagents. A composition comprising omega fatty acids and three of thefollowing: one or more emulsifying agents, one or more protease enzymes,one or more soluble calcium phosphate remineralizing agents, one or morewhitening agents. A composition comprising omega fatty acids, one ormore emulsifying agents, one or more protease enzymes, one or moresoluble calcium phosphate remineralizing agents, and one or morewhitening agents.

A composition comprising emu oil and one or more emulsifying agents. Acomposition comprising emu oil and one or more protease enzymes. Acomposition comprising emu oil and one or more soluble calcium phosphateremineralizing agents. A composition comprising emu oil and one or morewhitening agents. A composition comprising emu oil and two of thefollowing: one or more emulsifying agents, one or more protease enzymes,one or more soluble calcium phosphate remineralizing agents, one or morewhitening agents. A composition comprising emu oil and three of thefollowing: one or more emulsifying agents, one or more protease enzymes,one or more soluble calcium phosphate remineralizing agents, one or morewhitening agents. A composition comprising emu oil, one or moreemulsifying agents, one or more protease enzymes, one or more solublecalcium phosphate remineralizing agents, and one or more whiteningagents.

The above compositions are formulated as single layer tablets, bilayertablets or as any one of the formulations described hereinabove.

Example 9

The composition of the present application is administered to a subjector subjects suffering from xerostomia and/or hyposalivation. Thecomposition increases salivary flow in the subject(s). The compositionalso reduces the subjective sensation of dry mouth in the subject(s).The composition of the present application is administered to asubject's teeth. The composition whitens the subject's teeth.

The bilayer tablet composition of the present application comprising oneor more whitening agents in the rapidly disintegrating layer and emu oilis administered to a subject or subjects suffering from xerostomiaand/or hyposalivation. The bilayer tablet composition increases salivaryflow in the subject(s). The composition also reduces the subjectivesensation of dry mouth in the subject(s). The bilayer tablet compositionof the present application comprising one or more whitening agents inthe rapidly disintegrating layer and emu oil is administered to asubject's teeth. The bilayer tablet whitens the subject's teeth.

The bilayer tablet composition of the present application comprising oneor more whitening agents in the rapidly disintegrating layer isadministered to a subject's teeth. The bilayer tablet whitens thesubject's teeth.

Example 10

A single first oral care composition of the present application followedby five second oral care compositions of the present application areadministered over 24 hours to a subject suffering from xerostomia of theoral cavity and pharynx. The composition increases salivary flow in thesubject(s). The composition also reduces the subjective sensation of drymouth in the subject(s).

A single first oral care composition of the present application followedby five second oral care compositions of the present application areadministered over 24 hours to a subject suffering from mucositis of theoral cavity and pharynx. The compositions treat the subject sufferingfrom mucositis of the oral cavity and pharynx.

DISCUSSION

The composition disclosed herein relate to a stable, multi-component,solid dosage form for use in dental therapy that delivers an effectivecombination of emu oil, a whitening/cleansing agent, a protease enzyme,a re-mineralizing agent, and an emulsifying agent in the oral cavity.The combination of ingredients have been formulated and processed into abilayer tablet. No immediate signs of incompatibility in the dosage formitself were evident. There is considerable flexibility in the tablet interms of both composition, weight, and the weight of the layers, i.e.the slowly eroding later and the disintegrating layer. However, theconcentration of emu oil that can be accommodated in this dosage form is15% or less (based on the slow eroding layer). Incorporation of thelecithin was accomplished by dissolving the surfactant in the Emu oil.This approach required high temperature. However, alternative processingapproaches are available.

The bilayer tablet is described in FIGS. 1 and 2. The tablet consistsessentially of a rapidly disintegrating layer containing thewhitening/cleansing agent (i.e., carbamide peroxide) and anon-disintegrating slow eroding “lozenge-like” layer that contains theother components. The bilayer tablet creates a physical separation ofthe oxidizer from other product components in the dosage form. Thisfeature is especially desirable considering that the peroxide may beincompatible with the other agents (i.e. papain).

When placed in the oral cavity, the saliva causes rapid disintegrationof the disintegrating layer, creating a liquid environment with aneffective level of free hydrogen peroxide. Simultaneously, the secondlayer, which contains the other components, including emu oil and thepapain, begins to slowly erode. The duration of the whitening/cleansingaction of the peroxide is relatively short, so exposure of the othercomponent subject to oxidative degradation is limited and release ofthese ingredients is sustained.

REFERENCES

-   Anneroth G, Nordenram G, Bengtsson S. (1980) Effect of saliva    stimulants (Hybrin and malic acid) on cervical root surfaces in    vitro. Scand J Dent Res. 88, 214-8.-   Borges B. C. et al. (2010) Xerostomia and hyposalivation: a    preliminary report of their prevalence and associated factors in    Brazilian elderly diabetic patients. Oral Health Prev. Dent. 8, 2,    153-158.-   Cassolato S F, Turnbull R S. (2003) Xerostomia: clinical aspects and    treatment. Gerodontology. 20, 64-77.-   Davies A N. (2000) A comparison of artificial saliva and chewing gum    in the management of xerostomia in patients with advanced cancer.    Palliat Med. 14, 197-203.-   Hochberg M C, Tielsch J, Munoz B, et al. (1998) Prevalence of    symptoms of dry mouth and their relationship to saliva production in    community dwelling elderly: the SEE project. J Rheumatol 25,    486-4891.-   Nederfors, T. (1996) Xerostomia: prevalence and pharmacotherapy.    With special reference to beta-adrenoceptor antagonists. Swed Dent J    Suppl. 116, 1-70.-   Nederfors T, Isaksson R, Mornstad H, Dahlof C. (1997) Prevalence of    perceived symptoms of dry mouth in an adult Swedish    population-relation to age, sex and pharmacotherapy. Community Dent    Oral Epidemiol, 25, 211-216.-   Narhi T O, Meurman J H, Ainamo A. (1999) Xerostomia and    hyposalivation: causes, consequences and treatment in the elderly.    Drugs & Aging 15, 103-116.-   Orellana M F, Lagravere M O, Boychuk D G J, Major P W,    Flores-Mir C. (2006) Prevalence of xerostomia in population-based    samples: a systematic review. Journal of public health dentistry 66,    2, 152-158.-   Scully C, Bagan J V. (2004) Adverse drug reactions in the orofacial    region. Crit Rev Oral Biol Med. 15, 221-39.-   Silvestre-Donat F J, Miralles-Jorda L, Martinez-Mihi V. (2004)    Protocol for the clinical management of dry mouth. Med Oral. 9,    273-9.

What is claimed is:
 1. An oral care composition comprising: a) emu oil; and one or more of the following: b) one or more emulsifying agents; c) one or more protease enzymes; d) one or more soluble calcium phosphate remineralizing agents; e) one or more whitening agents.
 2. The composition of claim 1 comprising: a) emu oil; and two or more of the following: b) one or more emulsifying agents; c) one or more protease enzymes; d) one or more soluble calcium phosphate remineralizing agents; e) one or more whitening agents.
 3. The composition of claim 2 comprising: a) emu oil; and three or more of the following: b) one or more emulsifying agents; c) one or more protease enzymes; d) one or more soluble calcium phosphate remineralizing agents; e) one or more whitening agents.
 4. The composition of claim 3 comprising: a) emu oil; b) one or more emulsifying agents; c) one or more protease enzymes; d) one or more soluble calcium phosphate remineralizing agents; e) one or more whitening agents.
 5. The composition of claim 4, wherein one or more of the protease enzymes are selected from the group consisting of papain, trypsin, chymotrypsin, aminopeptidase, carboxypeptidase, pepsin, and cathepsin.
 6. The composition of claim 4, wherein the one or more whitening agents are selected from the group consisting of carbamide peroxide and hydrogen peroxide.
 7. The composition of claim 4, wherein the one or more soluble calcium phosphate remineralizing agents are selected from the group consisting of dibasic calcium phosphate, monocalcium phosphate, tricalcium phosphate, and tetracalcium phosphate.
 8. The composition of claim 7, wherein the one or more emulsifying agents are phospholipids.
 9. The composition of claim 8, wherein the phospholipids are lecithin.
 10. The composition of claim 4, wherein the composition further comprises an isomalt.
 11. The composition of claim 10, wherein the isomalt is selected from the group consisting of galenIQ™ 720 and galenIQ™
 721. 12. The composition of claim 4, wherein the composition further comprises a disintegrating agent.
 13. The composition of claim 12, wherein the disintegrating agent is crospovidone.
 14. The composition of claim 4, wherein the composition further comprises magnesium stearate.
 15. The composition of claim 4, wherein the composition further comprises glycerin.
 16. The composition of claim 4, wherein the composition further comprises fluoride.
 17. The composition of claim 4, wherein the remineralizing agent is white in color.
 18. The composition of any one claims 1-17, wherein the composition is formulated as a tablet, a bilayer tablet, a multilayer tablet, chewing gum, a toothpaste, a lozenge, a powder, a gel, a viscous gel, an ointment, a cream, a liquid, a mouthwash, or a candy.
 19. The composition of claim 18, wherein the composition is formulated as a bilayer tablet.
 20. The composition of claim 19, wherein the bilayer tablet comprises a rapidly disintegrating layer and a slowly eroding layer.
 21. The composition of claim 20, wherein the one or more whitening agents are present only in the rapidly disintegrating layer.
 22. The composition of claim 20, wherein the emu oil and the one or more proteases are present only in the slowly eroding layer.
 23. The composition of claim 20, wherein the one or more whitening agents are present only in the rapidly disintegrating layer; and the emu oil and the one or more proteases are present only in the slowly eroding layer.
 24. The composition of claim 23, wherein the rapidly disintegrating layer comprises carbamide peroxide in an amount between 0.1 to 10.0% by weight.
 25. The composition of claim 24, wherein the rapidly disintegrating layer comprises carbamide peroxide in an amount of 1.0% by weight.
 26. The composition of claim 23, wherein the slowly eroding layer comprises emu oil in an amount between 0.1 to 15% by weight.
 27. The composition of claim 26, wherein the slowly eroding layer comprises emu oil in an amount of 10% by weight.
 28. The composition of claim 23, wherein the slowly eroding layer comprises papain in an amount between 0.1 to 20% by weight.
 29. The composition of claim 27, wherein the slowly eroding layer comprises papain in an amount of 10% by weight.
 30. A method of treating a subject suffering from xerostomia which comprises administering to the subject, in an amount effective to treat the xerostomia, a composition of any one of claims 1-29.
 31. The method of claim 30, wherein the composition further whitens teeth in the subject's mouth.
 32. The method of claim 30, wherein the composition further remineralizes teeth in the subject's mouth.
 33. The method of claim 30, wherein the composition further whitens and remineralizes teeth in the subject's mouth.
 34. The method of claim 30, wherein the composition further reduces dental sensitivity of the subject.
 35. The method of claim 30, wherein the composition further treats dental caries of the subject.
 36. The method of any one of claims 30-35, wherein the subject is a human.
 37. The method of any one of claims 30-35, wherein the subject is a non-human animal.
 38. The method of claim 36, wherein the subject has an autoimmune disease, diabetes, Sjögren's syndrome, or has recently undergone radiation therapy or chemotherapy.
 39. The method of claim 36, wherein the subject is concurrently taking one or more medications that causes xerostomia.
 40. An oral care composition for whitening teeth comprising one or more whitening agents, wherein the composition is formulated as a bilayer tablet comprising: (i) a rapidly disintegrating layer; and (ii) a slowly eroding layer, wherein the one or more whitening agents are each oxidizing agents and are each present only in the rapidly disintegrating layer.
 41. The composition of claim 40, wherein the one or more whitening agents are selected from the group consisting of carbamide peroxide and hydrogen peroxide.
 42. The composition of claim 41, wherein the whitening agent is carbamide peroxide and is present in an amount between 0.1 to 10.0% by weight of the disintegrating layer.
 43. The composition of claim 41, wherein the whitening agent is carbamide peroxide and is present in an amount of 1.0% by weight of the disintegrating layer.
 44. The composition of claim 40, further comprising one or more of the following: a) emu oil; b) one or more emulsifying agents; c) one or more protease enzymes; d) one or more soluble calcium phosphate remineralizing agents.
 45. The composition of claim 44, further comprising two or more of the following: a) emu oil; b) one or more emulsifying agents; c) one or more protease enzymes; d) one or more soluble calcium phosphate remineralizing agents.
 46. The composition of claim 45, further comprising three or more of the following: a) emu oil; b) one or more emulsifying agents; c) one or more protease enzymes; d) one or more soluble calcium phosphate remineralizing agents.
 47. The composition of claim 46, further comprising each of the following: a) emu oil; b) one or more emulsifying agents; c) one or more protease enzymes; d) one or more soluble calcium phosphate remineralizing agents.
 48. The composition of claim 40, further comprising: a) emu oil; and one or more of the following: b) one or more emulsifying agents; c) one or more protease enzymes; d) one or more soluble calcium phosphate remineralizing agents.
 49. The composition of claim 47, wherein the emu oil, the one or more emulsifying agents, and the one or more protease enzymes are present only in the slowly eroding layer.
 50. The composition of claim 47, wherein the one or more soluble calcium phosphate remineralizing agents are present only in the rapidly disintegrating layer.
 51. A method of treating a subject suffering from xerostomia which comprises administering to the subject, in an amount effective to treat the xerostomia, a composition of claim
 48. 52. A method of whitening teeth in a subject's mouth which comprises administering to the subject's teeth, in an amount effective to whiten the teeth, a composition of any one of claims 40-50.
 53. An oral care composition comprising: a) one or more omega fatty acids; and one or more of the following: b) one or more emulsifying agents; c) one or more protease enzymes; d) one or more soluble calcium phosphate remineralizing agents; e) one or more whitening agents.
 54. The composition of claim 53 comprising: a) one or more omega fatty acids; and two or more of the following: b) one or more emulsifying agents; c) one or more protease enzymes; d) one or more soluble calcium phosphate remineralizing agents; e) one or more whitening agents.
 55. The composition of claim 54 comprising: a) one or more omega fatty acids; and three or more of the following: b) one or more emulsifying agents; c) one or more protease enzymes; d) one or more soluble calcium phosphate remineralizing agents; e) one or more whitening agents.
 56. The composition of claim 55 comprising each of the following: a) one or more omega fatty acids; b) one or more emulsifying agents; c) one or more protease enzymes; d) one or more soluble calcium phosphate remineralizing agents; e) one or more whitening agents.
 57. The composition of any one of claims 53-56, wherein the one or more omega fatty acids comprise omega-3 fatty acids or omega-6 fatty acids.
 58. The composition of claim 57, wherein the omega-3 fatty acid is alpha-linoleic acid and the omega-6 fatty acid is gamma-linoleic acid.
 59. A method of treating a subject suffering from xerostomia which comprises administering to the subject, in an amount effective to treat the xerostomia, a composition of claim
 53. 60. A method of whitening teeth in a subject's mouth which comprises administering to the subject's teeth, in an amount effective to whiten the teeth, a composition of claim
 56. 